Natural killer (NK) cells and resting peripheral T cells are similar in many ways. Both populations demonstrate surface expression of CD2, CD8, LFA-1, and the intermediate affinity receptor for interleukin 2 (IL-2). The T-cell receptor (TCR) zeta chain is also component of the low affinity Fc receptor complex (CD16) of NK cells, suggesting that the receptor- mediated signal transduction in these cells is similar as well. Moreover, it is known that like T cells, NK express the src-family tyrosine kinases and the non-src, zeta-associated kinase, ZAP7O. Despite the similarities between NK and T cells there are important differences. Unlike T cells, resting NK spontaneously mediate CD16- independent killing of both tumor and virally-infected cells and NK cells constitutively express lytic molecules such as perforin whereas these genes ar inducible in T cells. Additionally, NK cells are capable of producing several cytokines including interferon-gamma when stimulated with PMA, ionomycin, or IL-2 alone, whereas T cells require combinations of these signals. Taken together these differences in function between NK and peripheral T cells suggest that NK have a lower threshold for responsiveness or are endogenously preactivated. However, the molecular basis for this NK-cell functional phenotype has not been elucidated. The work within this project investigates the biochemical and molecular basis for the functional and phenotypic differences between NK and T cells. This is being accomplished by determining the similarities and differences in the response of NK cells and T cells to pharmacological agents that act at various levels within signal transduction, comparing the status of the basal signal transduction apparatus in NK and T cells, and identifying and cloning genes likely to be involved in the maintenance of the NK phenotype.